The brain has the remarkable capability to change in response to experience. While the entire nervous system is highly labile during development, the cerebral cortex remains plastic throughout life. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech, for the use of devices such as cochlear implants, and for recovery after short-term deafness. These changes are thought to occur primarily at synapses, basic units of information processing and plasticity. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems which convey behavioral context to local cortical circuits. However, little is known about the interactions between synaptic inputs and release of neuromodulators in vivo, making it challenging to relate perceptual learning to plasticity in the auditory cortex or other brain areas. Recently we have developed an approach to measuring the dynamics of synaptic modifications for hours, to more closely examine the links between auditory cortical plasticity and auditory perceptual learning. These experiments now allow the construction of a new framework for understanding general mechanisms of modulation and plasticity in a behavioral context. Specifically, we will study the physiological role of cortical and thalamic plasticity for enhancing auditory perception when sounds are paired with the powerful neuromodulator norepinephrine. Norepinephrine is important for selective attention, general arousal, and learning, is a major factor in stress, and s released by the locus coeruleus, a small and relatively homogeneous brainstem nucleus amenable to direct electrophysiological recordings. This proposal describes a series of electrophysiological and behavioral experiments that will examine the effects of locus coeruleus stimulation and norepinephrine release on the auditory cortex of adult rats. First, locus coeruleus stimulation will be paired with auditory stimuli in anesthetized animals for detailed intracellular recordings and mechanistic studies. Next, locus coeruleus pairing will be performed in awake animals to document the effects of neuromodulation and cortical plasticity on two forms of auditory behavior involving positive reward-based or negative stressful reinforcement. Finally, as preliminary data suggest that this form of plasticity is unusually long-lived and resistant to extinction, recordings will be made from locus coeruleus neurons to ask if this neuromodulatory center becomes sensitized to auditory stimulation to 'lock-in'changes of cortical circuitry via more continuous modulation. In summary, here we will use in vivo electrophysiological methods to ask how noradrenergic modulation, paired with acoustic input, leads to short- and long-term modifications of auditory thalamocortical circuitry and neuromodulatory release itself, to persistently improve perceptual abilities in behaving animals.

Public Health Relevance

Neuroplasticity - the ability of the brain to change in response to experience - is an essential feature of the auditory cortex, especially for speech and language learning as well as the successful use of devices such as cochlear implants. However, it is unclear how motivational state, behavioral training, and device usage drive plasticity within the central auditory system. The experiments to be performed in this proposal provide essential data on basic auditory neuroplastic mechanisms, required for improvement of prosthetic design and therapeutic strategies for treatment of deafness and language disorders.